Abstract

Contact repulsion of growing axons is an essential mechanism for spinal nerve patterning. In birds and mammals the embryonic somites generate a linear series of impenetrable barriers, forcing axon growth cones to traverse one half of each somite as they extend towards their body targets. This study shows that protein disulphide isomerase provides a key component of these barriers, mediating contact repulsion at the cell surface in chick half-somites. Repulsion is reduced both in vivo and in vitro by a range of methods that inhibit enzyme activity. The activity is critical in initiating a nitric oxide/S-nitrosylation-dependent signal transduction pathway that regulates the growth cone cytoskeleton. Rat forebrain grey matter extracts contain a similar activity, and the enzyme is expressed at the surface of cultured human astrocytic cells and rat cortical astrocytes. We suggest this system is co-opted in the brain to counteract and regulate aberrant nerve terminal growth.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

The following previously published data sets were used

Article and author information

Author details

  1. Geoffrey MW Cook

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Catia Sousa

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Julia Schaeffer

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Katherine Wiles

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Prem Jareonsettasin

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Asanish Kalyanasundaram

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Eleanor Walder

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Catharina Casper

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Serena Patel

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Pei Wei Chua

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Gioia Riboni-Verri

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Mansoor Raza

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Nol Swaddiwudhipong

    School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Andrew Hui

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Ameer Abdullah

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Saj Wajed

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. Roger J Keynes

    Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    rjk10@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1557-7684

Funding

Medical Research Council

  • Geoffrey MW Cook
  • Roger J Keynes

Wellcome

  • Geoffrey MW Cook
  • Roger J Keynes

Spinal Research

  • Julia Schaeffer

Trinity College, University of Cambridge

  • Roger J Keynes

University of Cambridge

  • Geoffrey MW Cook
  • Catia Sousa
  • Julia Schaeffer
  • Katherine Wiles
  • Prem Jareonsettasin
  • Asanish Kalyanasundaram
  • Eleanor Walder
  • Catharina Casper
  • Serena Patel
  • Pei Wei Chua
  • Gioia Riboni-Verri
  • Mansoor Raza
  • Nol Swaddiwudhipong
  • Andrew Hui
  • Ameer Abdullah
  • Saj Wajed
  • Roger J Keynes

Rosetrees Trust

  • Geoffrey MW Cook
  • Julia Schaeffer
  • Roger J Keynes

The Anatomical Society

  • Eleanor Walder

Amgen Foundation Summer Scholarship

  • Gioia Riboni-Verri

The authors declare that the funders provided research equipment and laboratory consumables, as well as salary support for Julia Schaeffer, Eleanor Walder and Gioia Riboni-Verri.

Reviewing Editor

  1. Carol A Mason, Columbia University, United States

Ethics

Animal experimentation: Chick embryos were used for this work, and all experiments were carried out at earlier developmental stages than those that require ethical approval.

Version history

  1. Received: December 19, 2019
  2. Accepted: May 23, 2020
  3. Accepted Manuscript published: May 26, 2020 (version 1)
  4. Accepted Manuscript updated: May 28, 2020 (version 2)
  5. Version of Record published: June 3, 2020 (version 3)
  6. Version of Record updated: June 12, 2020 (version 4)

Copyright

© 2020, Cook et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Geoffrey MW Cook
  2. Catia Sousa
  3. Julia Schaeffer
  4. Katherine Wiles
  5. Prem Jareonsettasin
  6. Asanish Kalyanasundaram
  7. Eleanor Walder
  8. Catharina Casper
  9. Serena Patel
  10. Pei Wei Chua
  11. Gioia Riboni-Verri
  12. Mansoor Raza
  13. Nol Swaddiwudhipong
  14. Andrew Hui
  15. Ameer Abdullah
  16. Saj Wajed
  17. Roger J Keynes
(2020)
Regulation of nerve growth and patterning by cell surface protein disulphide isomerase
eLife 9:e54612.
https://doi.org/10.7554/eLife.54612

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https://doi.org/10.7554/eLife.54612

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